Emerging science

BY NICK ZAGORSKI

ASBMB spotlights members from developing and emerging countries.

The American Society for Biochemistry and Molecular Biology, like the science it represents, truly is an international entity. Most of the society’s nearly 12,000 members have some connection to the global scientific community; some were born or trained abroad, others have mentored foreign students in their labs, and many have no doubt gone abroad for collaborations, sabbaticals or conferences. And of course, numerous ASBMB members carry out their research endeavors at institutions outside of the U.S. In recognition of this global reach, ASBMB Today once again presents profiles of some of our international scientists, this time focusing on those who deal with the challenges and opportunities of working in emerging scientific nations.

Albert Ketterman

“I’m not a big fan of heat and humidity,” Albert Ketterman confesses. Of course, making that confession from his office at Mahidol University’s Institute of Molecular Biosciences in Bangkok – where Ketterman has been since 1996 – might seem odd.

Although the tropical climes of Thailand admittedly were not an anticipated destination for Ketterman while he was an undergraduate biochemistry major at the University of California, Riverside, he has adapted well to the unusual circumstances that have brought him here.

Shortly after Ketterman began working in a lab at the University of California, San Francisco, the lab head was killed in an automobile accident, throwing the lab into chaos. Ketterman received an offer to work with Susan Pond, though she warned him that her husband might receive a department chair back in her native Australia, which would uproot her lab. Ketterman accepted, and before he knew it, he was a graduate student looking, on the other side of the Pacific Ocean, at the University of Queensland in Brisbane.

His graduate work entailed analyzing mammalian carboxylesterases and glutathione transferases, enzymes found in copious amounts in the liver that help break down various xenobiotics. That led to a postdoctoral position in the entomology department at the London School of Hygiene and Tropical Medicine, where Ketterman applied his knowledge of these conserved enzyme families to look at the role of GSTs and carboxylesterases in mosquito insecticide resistance.

But during a second postdoc at Imperial College London, Ketterman developed an interest in c-Jun N-terminal protein kinases, which respond to external stimuli and regulate processes like cell growth and apoptosis. “I had hoped to continue this area of research as faculty, but finding a position proved fruitless, because schools were looking for someone with 10 years of JNK experience as opposed to only two,” he says.

A Thai student in Ketterman’s lab overheard his plight and noted that Mahidol University had a job opening that would fit Ketterman’s skill and expertise with malaria enzymology, bringing the intrepid researcher to where he is today.

Siriraj Hospital and Mahidol University at Bangkok Noi Campus, Thailand.

And while the long distance didn’t bother Ketterman much at all – he grew up with a father in the Air Force and moved around constantly as a kid – the adjustment to Thailand’s research culture has taken a little longer.

Financial resources are indeed an issue, though it’s not a simple cut-and-dried proposition. “Budgets, grants and salaries may be much smaller in Thailand,” he says, “but so is the cost of labor, so getting bodies and hands into a lab is not hard at all.”

Ketterman adds that the Thai government has placed an emphasis on improving science education, so the labs are filled with eager students in addition to technicians and support staff.

Supplies tend to be more of a concern, however, as Ketterman has to pay prices for products that are similar to those paid by any U.S. lab. “The deliveries for these products can take a while, and we don’t really have the capabilities to handle frequent shipments,” he notes, “so you often have to plan far ahead in your experiments and anticipate what reagents you might need in a month or two.” That planning can be tricky, because given limited resources, funding priorities can shift abruptly.

In Ketterman’s case, he slowly shifted his GST work from malaria-related questions to a more general understanding of the enzyme family; as part of this effort, he recently pulled out all 41 GSTs identified in the Drosophila proteome for some comparative analysis.

But then engineers took over funding policy positions, and the government cut back basic research money to prioritize applied science. That meant Ketterman had to put his Drosophila GST collection on hold and find a new project.

So he teamed up with five other Mahidol investigators to study chikungunya virus, a tropical mosquito-borne pathogen that has re-emerged in the past few years.

The formation of such megagroups is an increasing trend in Thai research projects, as it provides a way to combine resources and use a variety of approaches to try to solve a problem more quickly. For his part, Ketterman will use his enzymology background to study a protease critical for chikungunya replication.

It’s a worthwhile task, for the virus has come back stronger than before. “It used to be the virus induced joint pain similar to arthritis, but it wasn’t too serious,” Ketterman says. “But now people are starting to die from chikungunya infections, so it’s become an active research area here.”

Hector Riveros-Rosas

A generation ago, protein scientists followed a straightforward paradigm: “one protein, one structure, one function.” But research now has revealed that moonlighting is not restricted to struggling Hollywood actors. Several protein families have developed a degree of promiscuity and can carry out activities not related to their main functions.

Hector Riveros-Rosas can take pride in the fact that he played a role in shifting this paradigm when he showed that alcohol-metabolizing enzymes might have evolved differently than people had thought.

It all began back when Riveros-Rosas was an undergraduate at the Universidad Nacional Autónoma de México. He was invited to participate in a research project studying the metabolic effects of chronic ethanol administration on isolated rat liver mitochondria.

That independent work solidified his interests in biochemistry, particularly alcohol metabolism, and he continued his research career at UNAM School of Medicine, first receiving his master's in 1996 and his doctorate in 2004.

During this time, while studying the properties of the main enzymes involved in alcohol metabolism, alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs), he observed that ADHs could utilize a huge diversity of alcohols as substrates. Other groups also had found that ADHs display higher catalytic efficiency for many endogenous substrates, such as retinol, steroids and dopamine.

“Thus, we proposed that the main physiological role of ADHs is the metabolism of these important endogenous substrates, and not ethanol oxidation,” he says.

To help validate this conclusion, Riveros-Rosas began to investigate the evolutionary history of ADHs. He and colleagues uncovered a big piece of evidence when they showed that the origin of ADHs predates the major natural dietary source of ethanol (fermentation of fruit sugar by yeast). Thus, ethanol availability could not be a selective force that directed the evolution of these proteins.

This discovery seemed unexpected given that the presence of ADHs in animals had been assumed to be a consequence of chronic exposure to ethanol. However, if the origin of the different ADHs predates the origin of angiosperms with fleshy fruits, then perhaps, ethanol metabolism was not an adaptive function in animals but just an incidental one.

Entrance to the Tlahuizcalpan building of the Faculty of Sciences of the National Autonomous University of Mexico.

“This opens up new ways of thinking about the deleterious effects of ethanol consumption,” says Riveros-Rosas. “People who drink heavily can acquire ethanol concentrations in their blood that reach the millimolar range. Even though ethanol is not the preferred substrate, this amount can significantly impair the metabolism of natural ADH substrates, which occur in the micromolar range.”

(Interestingly, like the moonlighting proteins he studies, Riveros-Rosas conducted a secondary project on the chemistry of air pollution with the National Institute of Ecology during this time; his team’s work provided some of the necessary data to push the Mexican government to prohibit the addition of lead to gasoline.)

Since starting his own lab several years back, Riveros-Rosas has been eagerly following up those initial studies with more detailed evolutionary analyses into the roles of ADHs and ALDHs in animals. His group also is employing bioinformatic and phylogenetic tools to obtain broader insight into the forces that drive enzyme evolution, using both ADHs and chromate transporters as model systems.

That such an intriguing discovery would come from Mexico is both surprising and expected, Riveros-Rosas thinks. While Mexico is considered an emerging country in research, he notes, it does have a respected biochemical history.

Back in the 19th century, Leopoldo Rio de la Loza, who founded Mexico’s National Academy of Medicine in 1864, was honored by many scientific societies in Europe and the United States for his pioneering work introducing chemistry into medicine. Later, Juan Roca Olivé, who spent several years working with Journal of Biological Chemistry co-founder John Abel at the Johns Hopkins University, brought the concept of physiological chemistry to Mexico and became the country’s first great biochemistry teacher.

At the same time, limited funding, equipment and even lab space did prevent research in Mexico from really blossoming. However, some economic changes in the past couple of decades have enabled the creation of many new research laboratories in several Mexican universities and also have improved the number of grants available.

“On the other hand, this increased research development has not yet reached the job sector,” Riveros-Rosas says. “Recent graduates have been encountering problems finding jobs, and this is discouraging new students from enrolling in master’s or Ph.D. programs.”

Still, Riveros-Rosas has been encouraged by the growth and believes the situation will balance out eventually. In his own life, the recently tenured professor is looking forward to leaving Mexico temporarily for a sabbatical to further enrich his training and get a taste of the outside world.

Veronica Okochi

ProfessorDepartment of BiochemistryUniversity of Lagos, Nigeria

Initially, Veronica Okochi’s scientific journey seemed on track to become another one of America’s immigration success stories.

She arrived in the United States in 1967 to begin her undergraduate studies, following in the tradition set by her two older brothers, both students at the University of Illinois. It was fortuitous timing for Okochi, as her native Nigeria was experiencing rising instability that would soon lead to civil war.

She enrolled at Barat College of the Sacred Heart in Lake Forest, Ill., and studied chemistry, a topic she had excelled at in secondary school. She also received the chance to work in the lab of noted clinical chemist Norbert Tietz at the Mount Sinai Hospital in Chicago, where she became fascinated with the relationship between chemistry and diseases, and sought to continue her education in this area.

After receiving her undergraduate degree in 1971, Okochi completed her Master of Science degree in clinical biochemistry at the University of Health Sciences/Chicago Medical School (today, Rosalind Franklin University of Medicine and Science), in 1974.

But at that point, Okochi made a big decision. “I chose to come home to Nigeria,” she says. “I knew it would not be easy, but I was inspired by the events I saw in the U.S. – the civil rights struggles and the teachings and hope of Martin Luther King. The civil war had ended, and Nigeria was rebuilding, and I had the zeal to give my service to my country.”

She found a job as a demonstrator (lecturer) in the biochemistry department at the University of Lagos, a staff position that also enabled her to pursue her doctoral degree. She began studying the membrane properties of the parasite Trypanosoma vivax, a serious livestock pathogen. “Trypanosome diseases not only cause tremendous human suffering in endemic areas, but they can render vast areas of grazing land unsuitable, causing serious economic and social consequences,” she explains.

Her hope was to gain more knowledge about the parasite’s biology and then explore the abundant medicinal flora in the region for potential antitrypanosomal agents. As Okochi completed her doctorate and rose to the rank of professor, her lab identified several promising trypanocides and conducted preliminary studies.

Unfortunately, Nigeria’s deficiencies in facilities and resources hindered the full-scale translation of her work for any commercial use. “The lack of infrastructure is a big challenge many Nigerian scientists face,” she says. “Our work does receive interest and sponsorship from more developed nations in those areas that have international dimensions, like HIV/AIDS and malaria, but that still leaves most of our research under-appreciated abroad.”

The University of Lagos is popularly known as Unilag.

However, hope is visible on the horizon, as the Nigerian government recently set out a policy goal to make Nigeria an industrially developed nation by 2020. And understanding that research is at the base of all development and progress, the government is making conscientious efforts to increase funding to the universities and research institutes across the country as part of its ambitious national goal.

“This is great news for the scientists here who are striving to make an impact in their research and help solve the problems of poverty, hunger and disease in our country,” claims Okochi.

Okochi also has shifted her focus, in part to join the biotechnology movement, but also to appease interests she developed through her travels. Over the years, she has accompanied her husband as he served at foreign missions in Japan and France, and she has had the privilege of working in places like Juntendo University in Tokyo and the Jacques Monod Institute in Paris. Studies with respiratory chain enzymes and protease inhibitors awakened a strong curiosity in enzymology.

Currently, Okochi is isolating pure cultures of fungi like Aspergillus niger and Penicillium chrysogenum from industrial plant wastes such as sawdust, corn cobs and sugar cane pulp and using them to produce enzymes like cellulases, pectinases and xylanases. In turn, these enzymes can hydrolyze the wood wastes into simple sugars for a variety of applications, such as animal feed or biofuels; she also has developed a technique to produce natural penicillin.

“I envisage this research as an environmentally friendly way to extract value from the volumes of cellulosic wastes that constitute a major source of pollution in our urban cities,” says Okochi, who now is looking at improving yields. “It’s important that as we develop as a nation, we do so in a responsible way.”

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COMMENTS:

Am really impressed about the above profile.but i have sometin to say i want to pursue a masters degree in clinical biochemistry it is sometin i love it alot and will need advice as to which university in nigeria offers the course i will appreciare it.my name is Nnamdi and wot are the requirement.i can be reached via email by nnamdirowland@ROCKETMAIL.COM.I Will appreciate it.

Dr. Riveros-Rosas, a young investigator, deserve much more future successes with this particular research.
Dr. Alfredo Saavedra-Molina